Omicron spike-specific binding antibodies reduce disease despite increased infection

In a recent study published in medRxiv* Preprint server, researchers have found that vaccine-induced antibodies that produce Fc effector activity against the severe acute respiratory syndrome coronavirus (SARS-CoV-2) omicron variant in three coronavirus disease 2019 (COVID-19) vaccinations. Investigate the ability of

Despite the rapid worldwide transmission of the SARS-CoV-2 Omicron variant, mortality has not increased, even in highly vaccinated populations. This suggests that immunological mechanisms other than neutralization may still provide protection against serious illness.

study: Omicron spike-specific antibody binding and Fc recognition conserved throughout the COVID-19 vaccine platform. Image Credits: Naeblys / Shutterstock.com

Utilization of Fc activity for Omicron

SARS-CoV-2 preferentially acquired a gradual collection of mutations within the S1 domain of spikes antigen, Within the receptor binding domain (RBD) or proximal. These mutations appear to enhance spike binding as the angiotensin converting enzyme 2 (ACE2) receptor continues to evolve and adapt to new hosts.

Both vaccine inductions Neutralizing antibody Monoclonal therapies are gradually losing their ability to neutralize the development of variant of concern (VOCs). This is primarily due to the fact that many of the powerful neutralizing antibodies attach to RBD to interfere with or prevent their interaction with ACE2. This loss of neutralization, coupled with the increase in ACE2 binding, is responsible for the worldwide increase in transmission events.

However, after infection, both direct and indirect cellular mechanisms contribute to pathogen control and clearance as a second line of defense. T cells, in particular, may be able to directly recognize and kill infected cells.

In addition, binding antibodies that bind to Fc receptors (FcRs) in immune cells can enhance the antiviral function of the innate immune system. This causes, among other things, rapid opson phagocytosis clearance, cytotoxicity of infected cells, or pro-inflammatory / anti-inflammatory mediators, all of which are influenza, Ebola, human immunodeficiency virus (HIV), and more recently. , SARS-CoV-2.

About research

In this study, researchers show that antibody isotype binding to Omicron RBD was reduced across the vaccine platform, while substantial Fc activity against Omicron spikes remained. This can contribute to the rapid control and elimination of viral infections and the reduction of disease severity.

To compare antibody responses elicited by various vaccines, samples were taken at peak immunogenicity from people who received the complete dosing regimen indicated by the manufacturer. Luminex multiplex was used to study antigen-specific antibody subclasses and isotypes, as well as FcγR binding.

Investigation result

Researchers have found a more dramatic loss of Omicron-RBD compared to the Omicron spike isotype / subclass. FcR binding was also seen throughout the vaccination platform. This is thought to be due to the preferential integration of changes in the S1 domain of the SARS-CoV-2 spike.

Vaccine-induced antibody binding to various SARS-CoV-2 mutants of concern. Individuals received a full-dose regimen of BNT162b2 (n = 11), mRNA-1273 (n = 14), or aluminum adjuvant inactivated particle vaccine CoronaVac (n = 13). Samples were taken at peak immunogenicity 2 weeks after the last dose. IgM, IgA1, and IgM for D614G (WT), Alpha (B1.117), Beta (B1.351), Delta (B.1.617.2), and Omicron (B1.529) variants of the receptor binding domain of concern. IgG1 binding titers (A) or full spikes (B) were measured by Luminex. The background corrected data is displayed and the negative value is set to 100 for graphing. The Kruskal-Wallis test, which used the Benjamini-Hochberg post-test to correct for multiple comparisons, was used to test for statistical differences between wild-type mutants and oxin titers. P-values ​​for significantly different features are shown above, showing a reduction in multiple changes in Omicron titer compared to wild type under each dataset.

Antibodies that mediate Fc activity, on the other hand, can bind to the entire surface of the antigen. This is different from neutralizing antibodies. Neutralizing antibody Spike protein Involved in attachment, RBD placement, or fusion.

The development of immune complexes and the organization of antibodies with Fc domains accessible to local immune cells are required for Fc activity. Omicron immunoglobulin G (IgG) that binds to the spike antigen was found to persist throughout the messenger ribonucleic acid (mRNA) and inactivated vaccination platforms.

Vaccine-induced Fcγ receptor-binding antibody profile across the SARS-CoV-2 mutant of concern. Individuals received a full-dose regimen of BNT162b2 (n = 11), mRNA-1273 (n = 14), or aluminum adjuvant inactivated particle vaccine CoronaVac (n = 13). Samples were profiled at peak immunogenicity 2 weeks after the last dose. To FcγR2a, FcγR2b, FcγR3a and FcγR3b of concern receptors D614G (WT), Alpha (B1.117), Beta (B1.351), Delta (B.1.617.2), and Omicron (B1.529) variants Binding-binding domain (A) or complete spike (B) -specific antibodies were determined by Luminex. The background corrected data is displayed and the negative value is set to 100 for graphing. The Kruskal-Wallis test, which used the Benjamini-Hochberg post-test to correct for multiple comparisons, was used to test for statistical differences between wild-type mutants and oxin titers. P-values ​​for significantly different features are shown above, showing a reduction in multiple changes in Omicron titer compared to wild type under each dataset.

This suggests that vaccine-induced antibodies may continue to opsonize the virus and virus-infected cells even after infection with Omicron. Neutralizing antibodies are likely to be important in preventing infection, but non-neutralizing antibodies that utilize Fc-biology may help maintain disease attenuation.

The three BNT162b2, mRNA-1273, and CoronaVac vaccines retained stronger binding to Omicron spike-specific FcgR2a, but FcgR2b and FcgR3b were selectively lost on all platforms. In humans, FcgR2b is the only low-affinity inhibitory receptor and is thought to contribute to the reduction of inflammatory activity.

Similarly, FcgR3b is expressed only in neutrophils and is thought to be important for the clearance of opsonized virus particles due to rapid phagocytosis. Continued binding to FcR2a and FcR3a can lead to continued particle clearance and killing of infected cells, but loss of FcR2b and FcR3b can lead to an increased inflammatory response.

In conclusion, identifying immunological pathways that lead to disease relief in the absence of neutralization is important for developing efficient pan VOC vaccines and increasing campaigns to combat the global COVID-19 pandemic. May provide information.

“”Neutralizing antibodies are likely to be the key to blocking infection, but non-neutralizing antibodies that can take advantage of Fc-biology may contribute to persistent disease attenuation... “

*Important Notices

medRxiv Publish preliminary scientific reports that should not be considered definitive as they have not been peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.